FDA Accepts Zilganersen New Drug Application for Priority Review in Alexander Disease

According to a new company update, the FDA has accepted for priority review Ionis Pharmaceuticals’ new drug application (NDA) for its investigational RNA-targeted therapy zilganersen as a potential treatment of patients with Alexander disease (AxD), a rare neurologic disorder. The agency has assigned a prescription drug user fee act (PDUFA) target action date of September 22, 2026.¹

“We are pleased the FDA has granted Priority Review for zilganersen. This decision recognizes the urgent need for treatment options and brings us one step closer to offering patients, who currently have no disease-modifying therapies, a potential treatment as quickly as possible,” an Ionis spokesperson told NeurologyLive^®. “If approved, zilganersen will be the first and only treatment for Alexander disease, marking a breakthrough for patients who are living with this rare, often fatal neurological condition.”

"Alexander disease is a devastating condition, commonly resulting in progressive motor and cognitive dysfunction, loss of independence and is often fatal. There are no approved disease-modifying treatments, underscoring the significant unmet need in this community,” Brett Monia, PhD, chief executive officer at Ionis, said in a statement.¹ “Priority Review designation underscores the urgent need for treatment options and will enable us to bring zilganersen to patients as quickly as possible.”

Study Findings

The NDA and priority review designation were supported by results from a pivotal phase 1-3 study (NCT04849741) evaluating zilganersen in children and adults living with AxD, in which the therapy met its primary end point of gait stabilization. Topline data indicated that zilganersen 50 mg demonstrated a statistically significant 33.3% mean difference in gait speed on the 10-Meter Walk Test compared with control at 61 weeks (P = .0412). The company reported that the treatment was generally well tolerated, with most adverse events (AEs) classified as mild or moderate in severity.²

In addition to the primary end point, zilganersen demonstrated consistent effects across key secondary measures, including patients’ self-identified Most Bothersome Symptom score, Patient Global Impression of Severity, Patient Global Impression of Change, and Clinician Global Impression of Change. According to Ionis, the data suggest slowed disease progression, stabilization, or improvement across these patient- and clinician-reported outcomes. The safety profile was reported as favorable, with a numerically lower incidence of serious adverse events in the zilganersen group compared with the control group.

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“These unprecedented results highlight the potential of zilganersen to create new possibilities for people living with Alexander disease, a devastating, progressive and often fatal condition that most commonly begins in early childhood and can take away fundamental functions like walking, speaking and swallowing,” Holly Kordasiewicz, PhD, senior vice president of neurology, Ionis, said in a statement.² “These data demonstrate the promise of zilganersen to potentially transform the future treatment landscape for this condition and reinforce the power of our technology to address neurological diseases by directly targeting the underlying cause. We are deeply grateful to the patients, families and researchers whose participation has helped make this progress possible."

Study Design

The pivotal trial was a global, multicenter, randomized, double-blind, controlled, multiple-ascending dose study that enrolled 54 participants aged 1.5 to 53 years across 13 sites in 8 countries. Most of the participants in the study were children, reflecting the early onset of AxD. Investigators randomized patients 2:1 to receive zilganersen or control for 60 weeks, with dosing administered every 12 weeks. The study included 2 dose cohorts (25 mg and 50 mg), with the 50-mg cohort designated as the pivotal dose group.

After the double-blind period, all eligible participants entered an open-label phase, followed by a 120-week long-term extension. The study’s primary end point was the percent change from baseline in gait speed as measured by the 10MWT, while key secondary end points were based on patient- and clinician-reported symptom assessments. Ionis noted that additional data from the pivotal study are expected to be presented at the 2026 American Academy of Neurology (AAN) Annual Meeting, held April 18-22, in Chicago, Illinois.

Zilganersen, an investigational antisense oligonucleotide therapy for the treatment of AxD, is designed to reduce production of glial fibrillary acidic protein, which accumulates as a result of disease-causing variants in the GFAP gene. The FDA previously granted zilganersen fast track designation in 2024 and breakthrough therapy designation in 2025, and the European Medicines Agency granted orphan drug designation in 2019.^3,4

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REFERENCES
1. Ionis announces zilganersen New Drug Application for Alexander disease (AxD) accepted by FDA for Priority Review. News release. Ionis Pharmaceuticals. March 23, 2026. Accessed March 23, 2026. https://ir.ionis.com/news-releases/news-release-details/ionis-announces-zilganersen-new-drug-application-alexander
2. Ionis announces positive topline results from pivotal study of zilganersen in Alexander disease. News release. Ionis Pharmaceuticals. September 22, 2025. Accessed March 23, 2026. https://ir.ionis.com/news-releases/news-release-details/ionis-announces-positive-topline-results-pivotal-study
3. Zilganersen granted U.S. FDA Fast Track designation for people living with Alexander disease. News release. Ionis Pharmaceuticals. October 1, 2024. Accessed March 23, 2026. https://ir.ionis.com/news-releases/news-release-details/zilganersen-granted-us-fda-fast-track-designation-people-living
4. Ionis receives U.S. FDA Breakthrough Therapy designation for zilganersen for Alexander disease (AxD). News release. Ionis Pharmaceuticals. December 2, 2025. Accessed March 23, 2026. https://ir.ionis.com/news-releases/news-release-details/ionis-receives-us-fda-breakthrough-therapy-designation